The present invention relates generally to the field of neurobiology and more specifically to a knockout mouse model.
The hereditary ataxias are a complex group of neurodegenerative disorders characterized by varying abnormalities of balance attributed to dysfunction or pathology of the cerebellum and cerebellar pathways. In many of these disorders, dysfunction or structural abnormalities extend beyond the cerebellum, and can involve basal ganglia function, oculo-motor disorders and neuropathy. The dominant spinocerebellar ataxias (SCAs) represent a heterogeneous group of disorders with a prevalence of familial cases of approximately 1 in 100,000.
A variety of genes and phenotypes have been identified to be associated with a family of neurodegenerative diseases, including SCA1, SCA2, Machado-Joseph disease (SCA3), SCA6, SCA7, Huntington disease, spinal bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. These diseases are associated with the expansion of a polyglutamine (polyQ) tract in the protein encoded by the respective disease genes.
Although the study of normal and diseased human brains can provide important insights into polyQ-associated disease pathogenesis, such observations are limited to the terminal stages of the disease process. Mouse models can circumvent this problem, but many mouse models of human polyQ diseases rely on the use of truncated constructs or very long polyQ tracts to produce neruodegeneration (Ikeda et al., Nature Genet., 13:196-202 (1996); Mangiarini et al., Cell, 87:493-506 (1996); Mangiarini et al., Nature Genet., 15:197-200 (1997); Davies et al., Phil. Trans. R. Soc. Lond. B Biol. Sci., 354:981-989 (1999)). In addition, several polyQ mouse models do not show prominent neuronal loss, a defining feature of human polyQ diseases. Furthermore, it is important to understand the function of the genes associated with these neurodegenerative diseases.
Thus, there exists a need for a non-human animal model of for the function of genes associated with neurodegenerative disease and methods of identifying therapeutic agents useful for treating conditions associated with these genes. The present invention satisfies this need and provides related advanatages as well.